Cyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxylic acid, 2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydro-2-[[7-methoxy-8-methyl-2-[4-(1-methylethyl)-2-thiazolyl]-4-quinolinyl]oxy]-5-methyl-4,14-dioxo-, ethyl ester, (2R,3aR,10Z,11aS,12aR,14aR)-

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

from 2011-09-15 to 2011-10-18

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Well documented GLP study performed according to OECD guideline 425, EPA OPPTS 870.1100 and a guideline of the Japanese Ministry of Agriculture, Forestry and Fisheries (Test Data for Registration of Agricultural Chemicals, Acute oral toxicity (2-1-1), 12 Nousan No 8147, Agricultural Production Bureau, November 24, 2000).

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2011

Report date:

2011

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agricultural Chemicals, Acute oral toxicity (2-1-1), 12 Nousan No 8147, Agricultural Production Bureau , November 24, 2000

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

up-and-down procedure

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

ethyl (1R,4R,6S,7Z,15R,17R)-17-({7-methoxy-8-methyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0^{4,6}]octadec-7-ene-4-carboxylate

EC Number:

618-843-3

Cas Number:

923604-57-3

Molecular formula:

C37H46N4O6S

IUPAC Name:

ethyl (1R,4R,6S,7Z,15R,17R)-17-({7-methoxy-8-methyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0^{4,6}]octadec-7-ene-4-carboxylate

Test material form:

solid

Details on test material:

- Name of test material (as cited in study reports): JNJ-38970191-AAA (T003009)
- Physical state: solid
- Appearance white solid

Test animals

Species:

rat

Strain:

other: CD (Crl:CD 'SD')

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 190-249 g
- Fasting period before study: overnight prior to and approximately four hours after dosing
- Housing: barriered rodent facility kept at positive pressure
- Diet (e.g. ad libitum): ad libitum except overnight prior to and approximately four hours after dosing
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5-7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23
- Humidity (%): 40-70
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: PEG 400, 1.2 eq NaOH 10 N and 0.3 eq HCl 12N

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 35, 110 and 300 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg

MAXIMUM DOSE VOLUME APPLIED: 300 mg/mL

- Rationale for the selection of the starting dose: As no previous toxicological information was available, the initial dose level was 175 mg/kg, in compliance with the study guidelines.

Doses:

175, 550 and 1500 mg/kg

No. of animals per sex per dose:

1 rat for 175 mg/kg
1 rat for 550 mg/kg
3 rats for 1500 mg/kg

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality : Cages of rats were checked at least twice daily for any mortalities; Clinical Observations : Observation soon after dosing and at frequent intervals for the remainder of Day 1. On subsequent days, animals were observed once in the morning and again at the end of the experimental day (morning only for Day 15); Bodyweight : The weight of each rat was recorded on Days 1 (prior to dosing), 8 and 15. Individual weekly bodyweight changes were calculated.
- Necropsy of survivors performed: yes (macroscopic evaluation of opened cranial, thoracic and abdominal cavities)

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 1 500 mg/kg bw

Based on:

test mat.

Mortality:

No deaths during the study.

Clinical signs:

other: No clinical signs related to treatment throughout the study.

Gross pathology:

No abnormalities were noted in any animal at the macroscopic examination at study termination on Day 15.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The acute median lethal dose (LD50) of JNJ-38970191-AAA to rats was > 1500 mg/kg bodyweight. Although the acute oral toxicity test concluded on an unbounded LD50, the precautionnary principle triggers a classification category 4 for this substance.